EP0857173B1 - Meiose regulierende verbindungen. - Google Patents

Meiose regulierende verbindungen. Download PDF

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Publication number
EP0857173B1
EP0857173B1 EP96918629A EP96918629A EP0857173B1 EP 0857173 B1 EP0857173 B1 EP 0857173B1 EP 96918629 A EP96918629 A EP 96918629A EP 96918629 A EP96918629 A EP 96918629A EP 0857173 B1 EP0857173 B1 EP 0857173B1
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Prior art keywords
compound
hydrogen
bound
alkyl
carbon atoms
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French (fr)
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EP0857173A1 (de
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Frederik Christian Groenvald
Peter Faarup
Erling Guddal
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Novo Nordisk AS
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to the use of certain pharmacologically active for regulating the meiosis.
  • Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1 n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1 c DNA.
  • the meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly.
  • All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty.
  • the female has a stock of oocytes which is drawn upon until the stock is exhausted.
  • Meiosis in females is not completed until after fertilization, and results in only one ovum and two abortive polar bodies per germ cell.
  • only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.
  • MAS meiosis activating substance
  • MPS meiosis preventing substance
  • the compounds mentioned herein can be used for regulating the meiosis in oocytes and in male germ cells.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 are both hydrogen.
  • the compound of formula (I) above is a compound wherein one of R 1 and R 2 is hydrogen while the other is methyl.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 are both methyl.
  • the compound of formula (I) above is a compound wherein R 1 is branched or unbranched C 1 -C 6 alkyl, optionally substituted by halogen, hydroxy or cyano.
  • the compound of formula (I) above is a compound wherein R 2 is branched or unbranched C 1 -C 6 alkyl, optionally substituted by halogen, hydroxy or cyano.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 together designate methylene.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 , together with the carbon atom to which they are bound, form a cyclopropane ring.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 , together with the carbon atom to which they are bound, form a cyclopentane ring.
  • the compound of formula (I) above is a compound wherein R 1 and R 2 , together with the carbon atom to which they are bound, form a cyclohexane ring.
  • the compound of formula (I) above is a compound wherein R 3 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 3 is methylene.
  • the compound of formula (I) above is a compound wherein R 3 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 3 is methoxy or acetoxy.
  • the compound of formula (I) above is a compound wherein R 3 is halogen.
  • the compound of formula (I) above is a compound wherein R 3 is oxo.
  • the compound of formula (I) above is a compound wherein R 3 is hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton.
  • the compound of formula (I) above is a compound wherein R 3 , together with R 9 , designates an additional bond between the carbon atoms to which R 3 and R 9 are bound.
  • the compound of formula (I) above is a compound wherein R 3 , together with R 14 , designates an additional bond between the carbon atoms to which R 3 and R 14 are bound.
  • the compound of formula (I) above is a compound wherein R 4 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 4 is methylene.
  • the compound of formula (I) above is a compound wherein R 4 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 4 is methoxy or acetoxy.
  • the compound of formula (I) above is a compound wherein R 4 is oxo.
  • the compound of formula (I) above is a compound wherein R 4 is hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton.
  • the compound of formula (I) above is a compound wherein R 4 , together with R 13 , designates an additional bond between the carbon atoms to which R 4 and R 13 are bound.
  • the compound of formula (I) above is a compound wherein R 4 , together with R 15 , designates an additional bond between the carbon atoms to which R 4 and R 15 are bound.
  • the compound of formula (I) above is a compound wherein R 5 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 5 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein R 5 is methylene.
  • the compound of formula (I) above is a compound wherein R 5 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 5 is methoxy.
  • the compound of formula (I) above is a compound wherein R 5 is oxo.
  • the compound of formula (I) above is a compound wherein R 5 , together with R 6 , designates an additional bond between the carbon atoms to which R 5 and R 6 are bound.
  • the compound of formula (I) above is a compound wherein R 6 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 6 , together with R 14 , designates an additional bond between the carbon atoms to which R 6 and R 14 are bound.
  • the compound of formula (I) above is a compound wherein R 9 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 9 , together with R 10 , designates an additional bond between the carbon atoms to which R 9 and R 10 are bound.
  • the compound of formula (I) above is a compound wherein R 10 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 11 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 11 is alkoxy, aralkyloxy, alkoxyalkoxy or alkanoyloxyalkyl, each group comprising a total of up to 10 carbon atoms, preferably up to 8 carbon atoms.
  • the compound of formula (I) above is a compound wherein R 11 is C 1 -C 4 alkoxy.
  • the compound of formula (I) above is a compound wherein R 11 is methoxy.
  • the compound of formula (I) above is a compound wherein R 11 is ethoxy.
  • the compound of formula (I) above is a compound wherein R 11 is CH 3 OCH 2 O-.
  • the compound of formula (I) above is a compound wherein R 11 is pivaloyloxymethoxy.
  • the compound of formula (I) above is a compound wherein R 11 is an acyloxy group derived from an acid having from 1 to 20 carbon atoms.
  • the compound of formula (I) above is a compound wherein R 11 is an acyloxy group selected from the group comprising acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy, tert -butoxycarbonyloxy and ethoxycarbonyloxy.
  • R 11 is an acyloxy group selected from the group comprising acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy, tert -
  • the compound of formula (I) above is a compound wherein R 11 is sulphonytoxy.
  • the compound of formula (I) above is a compound wherein R 11 is phosphonyloxy.
  • the compound of formula (I) above is a compound wherein R 11 is oxo.
  • the compound of formula (I) above is a compound wherein R 11 is halogen.
  • the compound of formula (I) above is a compound wherein R 11 is hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton.
  • the compound of formula (I) above is a compound wherein R 11 , together with R 12 , designates an additional bond between the carbon atoms to which R 11 and R 12 are bound.
  • the compound of formula (I) above is a compound wherein R 12 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 12 is C 1 -C 3 alkyl.
  • the compound of formula (I) above is a compound wherein R 12 is C 1 -C 3 alkoxy.
  • the compound of formula (I) above is a compound wherein R 12 is halogen.
  • the compound of formula (I) above is a compound wherein R 13 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 13 , together with R 14 , designates an additional bond between the carbon atoms to which R 13 and R 14 are bound.
  • the compound of formula (I) above is a compound wherein R 14 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 15 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 15 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein R 15 is methylene.
  • the compound of formula (I) above is a compound wherein R 15 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 15 is methoxy or acetoxy.
  • the compound of formula (I) above is a compound wherein R 15 is oxo.
  • the compound of formula (I) above is a compound wherein R 16 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 16 is C 1 -C 3 alkyl.
  • the compound of formula (I) above is a compound wherein R 16 is methylene.
  • the compound of formula (I) above is a compound wherein R 16 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 16 is methoxy.
  • the compound of formula (I) above is a compound wherein R 16 is oxo.
  • the compound of formula (I) above is a compound wherein R 16 , together with R 17 , designates an additional bond between the carbon atoms to which R 16 and R 17 are bound.
  • the compound of formula (I) above is a compound wherein R 17 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 17 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 18 and R 19 are both hydrogen.
  • the compound of formula (I) above is a compound wherein R 18 and R 19 are both fluoro.
  • the compound of formula (I) above is a compound wherein one of R 18 and R 19 is fluoro and the other is hydrogen.
  • the compound of formula (I) above is a compound wherein R 25 is hydrogen.
  • the compound of formula (I) above is a compound wherein R 25 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein R 25 is methylene.
  • the compound of formula (I) above is a compound wherein R 25 is hydroxy.
  • the compound of formula (I) above is a compound wherein R 25 is oxo.
  • the compound of formula (I) above is a compound wherein A is a carbon atom.
  • the compound of formula (I) above is a compound wherein A is a carbon atom and R 7 is hydrogen.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 7 is hydroxy.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 7 is fluoro.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 7 , together with R 8 , designates an additional bond between the carbon atoms to which R 7 and R 8 are bound.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 8 is hydrogen.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 8 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 8 is methylene.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 8 is halogen.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 20 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 20 is trifluoromethyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 20 is C 3 -C 6 cycloalkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 21 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 21 is C 1 -C 4 hydroxyalkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 21 is C 1 -C 4 haloalkyl containing up to three halogen atoms.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 21 is acetoxymethyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom R 21 is methoxymethyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom and R 21 is C 3 -C 6 cycloalkyl.
  • the compound of formula (I) above is a compound wherein A is a carbon atom and R 20 and R 21 , together with the carbon atom to which they are bound, form a C 3 -C 6 cycloalkyl ring, preferably a cyclopropyl ring, a cyclopentyl ring or a cyclohexyl ring.
  • the compound of formula (I) above is a compound wherein A is a nitrogen and R 7 designates a lone pair of electrons.
  • the compound of formula (I) above is a compound wherein A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is hydrogen.
  • the compound of formula (I) above is a compound wherein A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is C 1 -C 4 alkyl.
  • the compound of formula (I) above is a compound wherein A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is oxo.
  • the compound of formula (I) above is a compound wherein A is a nitrogen atom, R 7 designates a lone pair of electrons and R 20 and R 21 , independently, are selected from the group comprising C 1 -C 4 alkyl, cyclopropyl, cyclopentyl and cyclohexyl.
  • the present invention relates to the use of a 15 specific compounds mentioned in claim 1 below as a medicament, in particular as a medicament for use in the regulation of meiosis.
  • the compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
  • the expression "regulating the meiosis” is used to indicate that certain of the compounds of the invention can be used for stimulating the meiosis in vitro, in vivo, or ex vivo .
  • the compounds which may be agonists of a naturally occurring meiosis activating substance can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males.
  • Other compounds of the invention which may be antagonists of a naturally occurring meiosis activating substance, can be used for regulating the meiosis, preferably in vivo , in a way which makes them suited as contraceptives.
  • the "regulation" means partial or total inhibition.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the inhibition of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the stimulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
  • the present invention relates to the use ex vivo of a compound of formula (I) above in the inhibition of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
  • the present invention relates to a method of regulating the meiosis in a mammalian germ cell which method comprises ex vivo administering an effective amount of a compound of formula (I) above to a germ cell in need of such a treatment.
  • the present invention relates to a method wherein the germ cell the meiosis of which is to be regulated by means of a compound of formula (I) above is an oocyte.
  • the present invention relates to a method of regulating the meiosis in an oocyte wherein a compound of formula (I) above is administered to the oocyte ex vivo .
  • the present invention relates to a method of regulating the meiosis of a male germ cell by administering ex vivo a compound of formula (I) above to the cell.
  • the present invention relates to a method whereby mature male germ cells are produced by administering in vitro a compound of formula (I) above to testicular tissue containing immature cells.
  • C 1 -C 3 alkyl designates an alkyl group having from one to three carbon atoms; preferred examples are methyl, ethyl and propyl, more preferred methyl and ethyl.
  • C 1 -C 4 alkyl designates an alkyl group having from one to four carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl and butyl, more preferred methyl and ethyl.
  • C 1 -C 6 alkyl designates an alkyl group having from one to six carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl, butyl, tert -butyl, pentyl and hexyl, more preferred methyl, ethyl, propyl, isopropyl, butyl and tert -butyl, still more preferred methyl and ethyl.
  • C 1 -C 3 alkoxy designates an alkoxy group having from one to three carbon atoms; preferred examples are methoxy, ethoxy and propoxy, more preferred methoxy and ethoxy.
  • halogen preferably designates fluoro and chloro, more preferred fluoro.
  • the compounds dealt with herein will influence the meiosis in oocytes as well as in male germ cells.
  • the compounds dealt with herein are used to stimulate the meiosis.
  • the compounds dealt with herein are used to stimulate the meiosis in humans.
  • the compounds dealt with herein are promising as new fertility regulating agents without the usual side effect on the somatic cells which are known from the hitherto used hormonal contraceptives which are based on estrogens and/or gestagens.
  • a meiosis inducing substance can be administered so as to prematurely induce resumption of meiosis in oocytes while they are still in the growing follicle, before the ovulatory peak of gonadotropins occurs.
  • the resumption of the meiosis can, for example, be induced a week after the preceding menstruation has ceased.
  • the resulting overmature oocytes are then most likely not to be fertilized. The normal menstrual cycle is not likely to be affected.
  • the meiosis indudng substance dealt with herein can be used in the treatment of certain cases of infertility in females, including women, for example, by administration thereof to the oocytes of a females who, due to an insufficient own production of meiosis activating substance, are unable to produce mature oocytes.
  • in vitro fertilization is performed, better results are achieved, when a compound dealt with herein is added to the medium in which the oocytes are kept.
  • contraception in females can also be achieved by use of a compound dealt with herein which inhibits the meiosis, so that no mature oocytes are produced.
  • contraception in males can be achieved by use of a compound dealt with herein which inhibits the meiosis, so that no mature sperm cells are produced.
  • compositions containing a compound of claim 1 may be any route which effectively transports the active compound to its site of action.
  • compositions which comprises at least one compound dealt with herein in connection with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for oral use, such compositions are preferably in the form of capsules or tablets.
  • compositions comprising a compound dealt with herein may further comprise carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art.
  • solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions. Such liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilization.
  • the liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the list above.
  • composition for transdermal administration of a compound of this invention may be provided in the form of a patch and a composition for nasal administration may be provided in the form of a nasal spray in liquid or powder form.
  • the dose of a compound of the invention to be used will be determined by a physician and will depend, inter alia , on the particular compound employed, on the route of administration and on the purpose of the use.
  • the 1 H-NMR spectrum (CDCl 3 ,d) showed characteristic signals at: 0.62 (s,3H), 1.03 (s,3H), 3.0 (dd,1H), 3.62 (m,1H), 7.52 (broad s,1H).
  • the 13 GNMR spectrum (CDCl 3 , 100.6 MHz) showed characteristic signals at: 69.9, 126.7, 149.8, 157.7.
  • the title compound was prepared by using a method analogous to a method described in J Chemical Research (miniprint) (1979) 4714-4755. Cholesta-8,14-diene-3 ⁇ -ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to -78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8,7 mmol) in 10 ml of methylenechloride was added at -78° C. The mixture was stirred and was then slowly heated to the room temperature. The reaction mixture was added 15 ml water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO 3 and then with water.

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Claims (8)

  1. Die Verwendung von einer der folgenden Verbindungen 7-Oxo-5α-cholesta-8,14-dien-3β-ol; 7α-Methyl-5α-cholest-8-en-3β, 7β-Diol; 3β-Hydroxy-5α-cholest-8-en-7-oxim; 3β-Acetoxy-7-oxo-5α-cholest-8-en; 3β-Acetoxy-7-oxo-5α-cholesta-8,14-dien; 7-Methylen-5α-cholest-9-en-3β-ol; 7-Methyl-5α-cholesta-6,8-dien-3β-ol; Cholesta-8,14-dien-5α-H-3-on; 3α-Fluorcholesta-8,14-dien; cholesta-2,8,14-trien; und cholesta-8,14-dien-5α(H)-3(E), (Z)-Oxim als Arzneimittel.
  2. Die Verwendung einer Verbindung der allgemeinen Formel (I)
    Figure 00370001
    wobei R1 und R2, unabhängig von einander, ausgewählt werden, aus der Gruppe, umfassend Wasserstoff und verzweigtes oder unverzweigtes C1-C6-Alkyl, welche mit Halogen, Hydroxy oder Cyan substituiert werden können, oder wobei R1 und R2 gemeinsam Methylen darstellen, oder zusammen mit dem Kohlenstoffatom, an welches sie gebunden sind, einen Cyclopropanring, einen Cyclopentanring oder einen Cyclohexanring bilden; R3 wird ausgewählt aus der Gruppe, umfassend Wasserstoff, Methylen, Hydroxy, Methoxy, Acetoxy, Oxo, =NOR26, wobei R26 ein Wasserstoff ist oder ein C1-C3-Alkyl, Halogen, und Hydroxy, und C1-C4-Alkyl, an das gleiche Kohlenstoffatom des Sterolskeletts gebunden ist, oder R3 bezeichnet, zusammen mit R9 oder R14, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R3 und R9 oder R14 gebunden sind; R4 ist ausgewählt aus der Gruppe, umfassend Wasserstoff, Methylen, Hydroxy, Methoxy, Acetoxy, Oxo, =NOR27, wobei R27 Wasserstoff ist oder C1-C3-Alkyl, Halogen, und Hydroxy und C1-C4-Alkyl, an das gleiche Kohlenstoffatom des Sterolskeletts gebunden, oder R4 bezeichnet, zusammen mit R13 oder R15, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R4 und R13 oder R15 gebunden sind; R5 ist aus einer Gruppe ausgewählt, umfassend Wasserstoff, C1-C4 Alkyl, Methylen, Hydroxy, Methoxy, Oxo, und =NOR22, worin R22 Wasserstoff oder C1-C3 Alkyl ist, oder R5 bezeichnet, zusammen mit R6, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R5 und R6 gebunden sind; R6 ist Wasserstoff oder R6 bezeichnet, zusammen mit R5 eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R5 und R6 gebunden sind; R9 ist Wasserstoff oder R9 bezeichnet, zusammen mit R3 oder R10, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R9 und R3 oder R10 gebunden sind; R10 ist Wasserstoff oder R10 bezeichnet, zusammen mit R9, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R10 und R9 gebunden sind; R11 ist ausgewählt aus der Gruppe, umfassend Hydroxy, Alkoxy, substituierte Alkoxy, Acyloxy, Sulphonyloxy, Phosphonyloxy, Oxo, =NOR28, wobei R28 Wasserstoff ist oder C1-C3 Alkyl, Halogen und Hydroxy und C1-C4 Alkyl an das gleiche Kohlenstoffatom des Scerolskeletts gebunden, oder R11 bezeichnet, zusammen mit R12, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R11 und R12 gebunden sind; R12 ist ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-C3 Alkyl, Vinyl, C1-C3 Alkoxy und Halogen, oder R12 bezeichnet, zusammen mit R11, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R12 und R11 gebunden sind; R13 ist Wasserstoff oder R13 bezeichnet, zusammen mit R4 oder R14, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R13 und R4 oder R14 gebunden sind; R14 ist eine Wasserstoff oder R14 bestimmt zusammen mit R3, R6 oder R13, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R14 und R3 oder R6 oder R13 gebunden sind; R15 ist ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-C4 Alkyl, Methylen, Hydroxy, Methoxy, Oxo und =NOR23, wobei R23 ein Wasserstoff oder C1-C3 Alkyl ist, oder R15 bezeichnet, zusammen mit R4, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R15 und R4 gebunden sind; R16 wird ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-C3 Alkyl, Methylen, Hydroxy, Methoxy, Oxo und =NOR24, wobei R24 ein Wasserstoff oder C1-C3 Alkyl ist, oder R16 bezeichnet, zusammen mit R17, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R16 und R17 gebunden sind; R17 ist Wasserstoff oder Hydroxy oder R17 bezeichnet, zusammen mit R16, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R17 und R16 gebunden sind; R18 und R19 sind, unabhängig voneinander, Wasserstoff oder Fluor, R25 ist ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-4 Alkyl, Methylen, Hydroxy und Oxo; A ist ein Kohlenstoffatom oder ein Stickstoffatom; falls A ein Kohlenstoffatom ist, wird R7 ausgewählt aus der Gruppe, umfassend Wasserstoff, Hydroxy und Flour, und R8 wird ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-C4 Alkyl, Methylen und Halogen, oder R7 bezeichnet, zusammen mit R8, eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche R7 und R8 gebunden sind; R20 wird ausgewählt aus der Gruppe, umfassend C1-C4 Alkyl, Trifluormethyl und C3-C6 Cycloalkyl und R21 wird ausgewählt aus der Gruppe, umfassend C1-C4 Alkyl, C1-C4 Hydroxyalkyl, C1-C4 Haloalkyl, enthalten bis zu drei Halogenatome, Methoxymethyl, Acetoxymethyl, und C3-C6 Cycloalkyl, oder R20 und R21 bilden zusammen mit dem Kohlenstoffatom, an welches sie gebunden sind, einen C3-C6 Cycloalkylring; und falls A ein Stickstoffatom ist, bezeichnet R7 ein einziges Elektronenpaar und R8 wird ausgewählt aus der Gruppe, umfassend Wasserstoff, C1-C4 Alkyl und Oxo; R20 und R21 sind, unabhängig von einander, C1-C4 Alkyl oder C3-C6 Cycloalkyl; mit der Bedingung, dass die Verbindung der allgemeinen Formel (I) nicht kumulierte Doppelbindungen hat und mit der weiteren Bedingung, dass die Verbindung nicht eine Verbindung der allgemeinen Formel (II)
    Figure 00400001
    ist, wobei R1* und R2*, unabhängig von einander, ausgewählt sind aus der Gruppe, umfassend Wasserstoff, verzweigtes oder unverzweigtes C1-C6 Alkyl, welches mit Halogen oder Hydroxy substituiert werden kann, oder wobei R1* und R2*, zusammen mit dem Kohlenstoffatom, an welches sie gebunden sind, einen Cyclopentanring oder Cyclohexanring bilden; R13* und R14* bezeichnen gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind, in welchem Fall R3* ein Wasserstoff ist und R6* und R5* entweder Wasserstoff sind oder gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind, bezeichnen; oder R3* und R14* bezeichnen gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind, in welchem Falle R13* Wasserstoff ist und R6* und R5* entweder Wasserstoff sind, oder sie bezeichnen gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind; oder R6* und R14* bezeichnen gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind, in welchem Falle R13*, R3* und R5* alle Wasserstoff sind; R8* und R7* sind Wasserstoff oder bezeichnen gemeinsam eine zusätzliche Bindung zwischen den Kohlenstoffatomen, an welche sie gebunden sind; und B* ist entweder Wasserstoff oder eine Acylgruppe, einschließend eine Sulphonylgruppe oder eine Phosphonylgruppe, oder eine Gruppe, welche zusammen mit dem übrig bleibenden Teil des Moleküls einen Ether bildet, und Ester und Ether davon können für die Zubereitung eines Medikaments für die Regulierung der Meiose verwendet werden.
  3. Die Verwendung gemäß des vorhergehenden Anspruches, worin die Verbindung irgendeine der folgenden Verbindung ist: 7-Oxo-5α-cholest-8-en-3β-ol; 7-Oxo-5α-cholesta-8, 14-dien-3β-ol; 7α-Methyl-5α-cholest-8-en-3β, 7β-diol; 11-Oxo-5α-cholest-8-en-3β-ol; 3β-Hydroxy-5α-cholest-8-en-7-oxim; 3β-Acetoxy-7-oxo-5α-cholest-8-en; 3β-Acetoxy-7-oxo-5α-cholesta-8,14-dien; 7-Oxo-5α-cholest-8-en-3β-yl Benzoat; 7-Methylen-5α-cholest-9-en-3β-ol; 7-Methyl-5α-cholesta-5,8-dien-3β-ol; 11-Oxo-5α-cholest-8-en-3β-yl-Benzoat; Cholesta-8,14-dien-5α-H-3-on; 3α-Fluotcholesta-8,14-dien; Cholesta-2,8,14-trien; und Cholesta-8,14-dien-5α(H)-3-(E), (Z)-oxim.
  4. Ein Verfahren zur Regulierung der Meiose in einer Säugetierkeimzelle, welches Verfahren das ex vivo Applizieren einer wirksamen Menge einer Verbindung der Formel (I), angegeben in Anspruch 2, in eine Keimzelle, die einer solchen Behandlung bedarf, umfasst, vorzugsweise eine Verbindung, angegeben in Anspruch 3.
  5. Ein Verfahren gemäß dem vorhergehenden Anspruch, worin die Keimzelle, deren Meiose reguliert werden muss, eine Oocyte ist.
  6. Ein Verfahren gemäß Anspruch 4, wobei eine Verbindung der Formel (I), angegeben in Anspruch 2, vorzugsweise eine Verbindung, angegeben in Anspruch 3, einer Oocyte ex vivo appliziert wird.
  7. Ein Verfahren gemäß Anspruch 4, wobei die Keimzelle, deren Meiose reguliert werden soll, eine männliche Keimzelle ist
  8. Ein Verfahren gemäß Anspruch 4, wobei männliche Keimzellen durch Applizieren einer Verbindung der Formel (I), angegeben in Anspruch 2, vorzugsweise einer Verbindung angegeben in Anspruch 3, in testikuläres Gewebe in vitro hergestellt werden.
EP96918629A 1995-06-23 1996-06-21 Meiose regulierende verbindungen. Expired - Lifetime EP0857173B1 (de)

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US9034859B2 (en) 2011-04-06 2015-05-19 Virginia Commonwealth University Sulfated oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
US10144759B2 (en) 2004-10-25 2018-12-04 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US10272097B2 (en) 2013-12-24 2019-04-30 Virginia Commonwealth University Uses of oxygenated cholesterol sulfates (OCS)

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IL139241A0 (en) * 1998-05-13 2001-11-25 Novo Nordisk As Meiosis regulating compounds
EP0957108A1 (de) * 1998-05-14 1999-11-17 Schering Aktiengesellschaft Ungesättigte Cholestan-derivate zur Regulierung von Meiose und pharmazeutische Präparate davon
WO1999067273A1 (en) * 1998-06-19 1999-12-29 Novo Nordisk A/S Meiosis regulating compounds
AU759344B2 (en) 1998-12-11 2003-04-10 Akzo Nobel N.V. 22S-hydroxycholesta-8, 14-diene derivatives with meiosis regulating activity
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ATE317266T1 (de) * 1999-02-24 2006-02-15 Novo Nordisk As In vitro methode zur synchronisation von oozytenreifung
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US9321802B2 (en) 2004-10-25 2016-04-26 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US10144759B2 (en) 2004-10-25 2018-12-04 Virginia Commonwealth University Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
US9034859B2 (en) 2011-04-06 2015-05-19 Virginia Commonwealth University Sulfated oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
US9480692B2 (en) 2011-04-06 2016-11-01 Virginia Commonwealth University Sulfated-oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
US10272097B2 (en) 2013-12-24 2019-04-30 Virginia Commonwealth University Uses of oxygenated cholesterol sulfates (OCS)

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NO976044D0 (no) 1997-12-22
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IL122609A0 (en) 1998-08-16
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NO314231B1 (no) 2003-02-17
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